The FDA is currently debating whether to approve testing of three procedures designed to enable women with a mitochondrial disease to produce healthy children.
Mitochondria are small structures within cells that supply the energy required for life. They are unusual in that they have their own DNA that produces some of the molecules required for energy metabolism. And when this mitochondrial DNA (mtDNA) has a mutation, medical conditions affecting energy production can result. A curiosity of mammalian biology is that all the mitochondria an individual has are inherited from the mother. So, if the mother carries a mutation in her mtDNA, her children will have the same mutation.
Proponents of conducting human experiments to generate “three-parent embryos” cast this procedure as a beneficent therapeutic approach to treat women with mitochondrial disease and allow them to bear healthy children. In reality, it is a macabre form of eugenic cloning, in which a human being with a medical condition is killed and his or her parts are used to create a new human being with an improved biological state.
Maternal Spindle Transfer
The procedures under consideration by the FDA fall into three general classes. The first, known as “Maternal Spindle Transfer,” would use an egg from the mother with the mitochondrial disease and a donor egg from a woman with healthy mitochondria. The nucleus of the donor’s egg would be replaced by the nucleus of the mother’s egg. This would create a “hybrid” egg, with the nuclear DNA from the mother and the cytoplasmic elements (including healthy mitochondria) from the donor. This hybrid egg would then be fertilized by the father’s sperm to create a “three-parent” human embryo: DNA from mother, DNA from father, and non-nuclear components of the egg (including mtDNA) from the donor.
Maternal Spindle Transfer is a risky experiment with an uncertain outcome. If either the mother’s nucleus or the donor’s egg is damaged, the resulting embryo may develop abnormally or die. Yet Maternal Spindle Transfer is essentially a manipulation of human cells, not human beings. Consequently, it is the least ethically problematic of the three proposals.
By contrast, the two other procedures under consideration (“Pro-Nuclear Transfer” and “Embryo Cell Nuclear Transfer”) involve the direct destruction of at least one embryo and the subsequent use of its parts to create a new, cloned embryo with superior biology. Given that human life begins at the moment of sperm-egg fusion, these procedures are both forms of eugenic cloning conducted at a very early stage of the human life span.
In Pro-Nuclear Transfer, a single-cell embryo is created using sperm and egg from the mother and father. This embryo has mutated mitochondria from the mother. At the same time, a second embryo is created using a donor egg with healthy mitochondria. These one-cell human embryos or zygotes are clearly human beings at the earliest stage of the natural lifespan. The “pro-nuclei” (nuclei derived from the sperm and egg) are removed from both embryos—killing them both. Then a new embryo is produced by transferring the pronuclei from the afflicted embryo to the healthy cytoplasm of the “host” embryo. This is a form of destructive human cloning; i.e. the nuclear DNA of one human being is used to create a genetic copy or "clone" of that individual by transfer to egg-derived cytoplasm from a donor, killing the original embryo and the donor in the process (see "Serious Ethical Concerns" below).
In this procedure, as in Maternal Spindle Transfer, there is risk of damaging the transferred nucleus or the “host” embryo, causing development of the resulting, cloned embryo to be abnormal. In addition, two embryos are created and then destroyed in the process of producing the third, cloned embryo. Finally, this procedure involves the intentional creation of a “defective” human being who is then destroyed so that a part of the body (the nucleus) can be used to clone a new human being, who is viewed as biologically superior. It is eugenic cloning.
Embryo Cell Nuclear Transfer
Embryo Cell Nuclear Transfer is similar to Pro-Nuclear Transfer, except that only one embryo is produced from the sperm and egg of the parents. This embryo is allowed to develop for a day or two before a nucleus from one of its cells is used to produce a new, cloned embryo by transferring it to a donor egg cell with healthy mitochondria that has had its own nucleus removed. The original embryo with the mitochondrial disease is then destroyed.
In this case, as in the two procedures above, there is a significant risk of damaging the egg cell or the transferred nucleus, resulting in abnormal or failed development of the resulting cloned embryo. And Embryo Cell Nuclear Transfer is also a form of eugenic cloning where a “defective” human being is destroyed to obtain desirable parts (in this case, a nuclear genome derived from both parents) to construct a superior human being.
In all three cases, a human being is produced using essential components from three parents: nuclear DNA from the two intended parents and egg cytoplasm from a donor.
Serious Ethical Concerns
Surprisingly, many people do not see an obvious problem with these proposals. A medical colleague of mine recently opined, “If you take the newly formed pronucleus and put it in a different ‘body’ (i.e., another woman’s egg), are you really destroying that embryo? The individual would still develop with almost all the same genetic traits, and would potentially survive longer if the therapy worked.”
Yet the view that transfer of an embryo’s nucleus is merely a “therapeutic” approach for treatment of disease is false. The embryo produced by this procedure is not just the original child of the parents, moved to a new cytoplasmic "environment." This would only be true if a human being were nothing more than his or her DNA, which is clearly not the case. While our unique DNA clearly determines many aspects of our individual characteristics, we are also greatly influenced by the specific, non-genetic composition of the egg that produced us. As explained in detail in a paper available here, many aspects of embryonic development, and therefore many aspects of the unique individual we end up being, depend on non-genetic components derived from the cytoplasm of the egg.
The importance of non-genetic factors in determining the unique character of a human individual is very clearly illustrated by “maternal effect mutations.” These mutations have no effect on the development or function of the mother, but specifically disrupt development of embryos derived from her eggs. The embryo may not even have the “bad” gene (only half of the mother’s genome is passed on to any one child), but embryonic development can still be profoundly affected by the molecules present in the egg itself. Many key developmental factors work like this—in both positive and negative ways. Therefore, all three of the procedures described above would indeed generate “three-parent embryos,” whose unique traits and human identity would reflect the genetic contributions of both mother and father as well as the critical, non-genetic contributions made by the egg donor.
In addition to the obvious ethical issues raised by eugenic cloning and destructive experimentation on human embryos, these procedures raise two other serious concerns. All three are highly likely to be unsafe for the resulting children, even the ones that are not deliberately destroyed and are not damaged by the procedure itself. Mitochondrial heteroplasmy, or the persistence of some mitochondria from both the mother and the donor egg, is a significant risk to any children produced by these techniques. In general, heteroplasmy is not a good thing, and in this case, it could also cause reappearance of the disease in the offspring of any woman produced by the “three-parent” approach, due to mitochondrial “founder effects” in oogenesis. Even a few “bad” mitochondria can become the dominant type in any one egg, causing the mitochondrial disease to recur in any child produced from that egg.
Second, these procedures are forms of “germ-line engineering” that alter the genetic makeup of future generations in a permanent way. We know that in nature, mtDNA and nuclear DNA “co-evolve” to work with each other in an efficient manner. In some species, incompatibility between the mitochondrial and nuclear genome significantly compromises the health of the individual.
All of the proposed methods of “treating” mitochondrial disease introduce a permanent and unnatural mismatch between the nuclear and the mitochondrial genome that will be inherited by all subsequent generations. This constitutes unethical, destructive experimentation on humans, with no guarantee of outcome for either the “patient” (the cloned embryo produced) or any of the offspring of that patient. This is an unwarranted approach that puts future generations at grave risk of unforeseen consequences, in addition to the clearly foreseen destruction of a class of “defective” humans in the hope of manufacturing “superior” offspring.
Maureen L. Condic is Associate Professor of Neurobiology and Anatomy at the University of Utah School of Medicine.